Oleanane-type triazole glycoside compounds and their use in preparing PTP1B inhibitors and antidiabetic drugs

Abstract

The present invention discloses an oleanane-type triazole glycoside compound and its application in the preparation of PTP1B inhibitors and anti-diabetic drugs. The structural formula of the compound is: wherein R represents a saccharide group, which is oleanolic acid C 28 The oleanane-type triazole glycoside is prepared by converting the 3-hydroxyl group of methyl n-aminohexanoate into a 4-pentynyl ester as the starting material, followed by a click reaction with an azidosugar compound to introduce different sugar units. Pharmacological activity tests have shown that the oleanane-type triazole glycoside has excellent inhibitory activity against protein tyrosine phosphatase 1B and can be studied and utilized as a novel PTP1B inhibitor and antidiabetic drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and particularly relates to an oleanane-type triazole glycoside compound and its application in the preparation of a PTP1B inhibitor and an anti-diabetic drug. Background Art

[0002] Diabetes mellitus (DM) is a chronic disease that is prevalent worldwide. With economic development, improved living standards and changes in eating habits, the prevalence rate has gradually increased, and it has become a major problem that plagues human health. According to data from the International Diabetes Federation (IDF), diabetes has caused 6.7 million deaths in 2021. As of 2021, one in ten people is a diabetic, and the total number of adult diabetic patients (20-79 years old) has reached 537 million. It is estimated that by 2030, this number will rise to 639 million, and by 2045, 783 million people will be troubled by diabetes. Protein tyrosine phosphatase 1B (PTP1B) has important cellular biological functions and has become a recognized important new target for anti-type 2 diabetes drugs. Because the amino acid sequence at the catalytic site of all PTPs is highly conserved, qualified PTP1B inhibitors must be highly selective, acting only on PTP1B to minimize adverse reactions. Furthermore, the catalytic site of PTP1B carries a high positive charge, which readily attracts negatively charged inhibitors. However, most competitive PTP1B inhibitors contain negatively charged polar groups, making them difficult to penetrate cell membranes. Therefore, the search for novel PTP1B inhibitors with high potency, selectivity, and excellent pharmaceutical properties holds significant research significance and promise.

[0003] Oleanolic acid is a natural pentacyclic triterpenoid compound with rich pharmacological activity. Studies have shown that oleanane compounds, as a new class of PTP1B inhibitors, have significant anti-type II diabetes activity and have become one of the hot topics in the field of anti-type II diabetes drug research. There are many reports on the modification of oleanolic acid to screen for PTP1B inhibitors in the prior art. For example, CN 108530508 A discloses an oleanane-type azaglycoside compound and its use in the preparation of anti-diabetic drugs. The compound is prepared by converting the 3-hydroxyl group of oleanolic acid C28-amino-n-hexanoic acid methyl ester into an amino group and then introducing different sugar units. Pharmacological activity tests show that the compound has excellent inhibitory activity against protein tyrosine phosphatase 1B. CN117720610 A discloses an oleanolic acid mannoside compound and its use in the preparation of anti-diabetic drugs. The compound is prepared by introducing a D-mannose group into the 3-hydroxyl group of oleanolic acid C28-amino-n-hexanoic acid methyl ester, and then converting the C6-OH of the D-mannose group into a fatty ester group or a heteroatom substituent, and leaving the hydroxyl groups at other positions naked or converted into acetyl groups. Pharmacological activity tests showed that this class of compounds exhibited strong inhibitory activity against protein tyrosine phosphatase 1B. With the exception of compounds 5, 12, 13, 20, and 21, the other compounds were significantly more effective than the positive control sodium orthovanadate and the most active compound 18 reported in CN 108530508 A. However, studies on the PTP1B inhibitory activity of oleanolic acid triazole glycoside compounds have not been reported. Summary of the Invention

[0004] The purpose of the present invention is to provide a new class of oleanane-type triazole glycoside compounds and a new use of the compound.

[0005] For the above purpose, the structural formula of the oleanane-type triazole glycoside compound provided by the present invention is as follows:

[0006]

[0007] wherein R is selected from any one of D-peracetylmannasyl, D-peracetylglucosyl, D-peracetygalactosyl, L-peracetyrhamnosyl, L-peracetyarabinosyl, D-peracetyarabinosyl, L-peracetyxylosyl, D-peracetyxylosyl, D-peracetylcellobiosyl, D-peracetygalactose (1→4)-D-peracetylglucosyl, D-peracetylglucosyl (1→4)-D-peracetylglucosyl, D-mannosyl, D-glucosyl, D-galactosyl, L-rhamnosyl, L-arabinosyl, D-arabinosyl, L-xylosyl, D-xylosyl, D-cellobiosyl, D-galactose (1→4)-D-glucosyl, and D-glucose (1→4)-D-glucosyl.

[0008] Furthermore, the above R is preferably β-D-peracetylated mannopyranosyl, β-D-peracetylated glucopyranosyl, β-D-peracetylated galactopyranosyl, α-L-peracetylated rhamnosyl, α-L-peracetylated arabinopyranosyl, β-D-peracetylated arabinopyranosyl, α-L-peracetylated xylopyranosyl, β-D-peracetylated xylopyranosyl, β-D-peracetylated cellobiosyl, β-D-peracetylated galactopyranosyl (1→4)-α-D-peracetylated glucopyranosyl, β-D-peracetylated glucopyranosyl, Any one of glucose (1→4)-β-D-peracetylated glucopyranosyl, β-D-mannopyranosyl, β-D-glucopyranosyl, β-D-galactopyranosyl, α-L-rhamnopyranosyl, α-L-arabinopyranosyl, β-D-arabinopyranosyl, α-L-xylopyranosyl, β-D-xylopyranosyl, β-D-cellobiosyl, β-D-galactopyranosyl (1→4)-α-D-glucopyranosyl, and β-D-glucopyranosyl (1→4)β-D-glucopyranosyl.

[0009] The synthesis method of the oleanane-type triazole glycoside compound of the present invention is as follows:

[0010] 1. Synthesis of compound 24

[0011] Compound 23 was reacted with 4-pentynoic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), and 4-dimethylaminopyridine (DMAP) in a molar ratio of 1:2-3:3-4:0.1-0.5 using dry dichloromethane as the solvent. The mixture was stirred at room temperature for 5-6 hours. After the reaction, the mixture was filtered, concentrated under reduced pressure to remove the solvent, and the concentrate was purified by silica gel column chromatography to obtain compound 24. The reaction equation is as follows:

[0012]

[0013] 2. Synthesis of oleanane-type triazole glycoside compounds

[0014] Compound 24 and azidosugar R-N3 were mixed in a molar ratio of 1:1.0-1.2 using tert-butanol as solvent; CuSO4 and sodium ascorbate (Na ascorbate) were mixed in a molar ratio of 1:1.5-2.5 using deionized water as solvent; the two solutions were then mixed and stirred at 35-45°C for 2-4 hours; after the reaction, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The ethyl acetate phases were combined, washed sequentially with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain compound A. The reaction equation is as follows:

[0015]

[0016] In the formula, R′ represents any one of D-peracetylmannasyl, D-peracetylglucosyl, D-peracetylglucosyl, L-peracetylglucosyl, L-peracetylarhamnosyl, L-peracetylarbinosyl, D-peracetylarbinosyl, L-peracetyxylosyl, D-peracetylcellobiosyl, D-peracetygalactosyl (1→4)-D-peracetylglucosyl, and D-peracetylglucosyl (1→4)-D-peracetylglucosyl.

[0017] The above compound A was dissolved in a mixed solvent of methanol and dichloromethane, and sodium methoxide was added to adjust the pH to 8.5-9.5. The mixture was stirred at room temperature for 30-40 minutes. The pH was adjusted to 7 using a cation exchange resin. The cation exchange resin was removed by filtration, and the solvent was removed by concentration under reduced pressure. The mixture was purified by silica gel column chromatography to obtain compound B. The reaction equation is as follows:

[0018]

[0019] In the formula, R″ represents any one selected from D-mannosyl, D-glucosyl, D-galactosyl, L-rhamnosyl, L-arabinosyl, D-arabinosyl, L-xylosyl, D-xylosyl, D-cellobiosyl, D-galactosyl (1→4)-D-glucosyl, and D-glucosyl (1→4)-D-glucosyl.

[0020] The present invention provides the use of the oleanane-type triazole glycoside compound in the preparation of PTP1B inhibitors and antidiabetic drugs. The oleanane-type triazole glycoside compound is prepared according to conventional pharmaceutical preparations and a pharmaceutically acceptable carrier according to conventional preparation processes of various preparations, and can be tablets, granules, or capsules.

[0021] The beneficial effects of the present invention are as follows:

[0022] The present invention uses oleanolic acid C 28 Oleanane-type triazole glycoside compounds were prepared by converting the 3-hydroxyl group of methyl n-aminohexanoate into a 4-pentynyl ester as the starting material. These compounds were then reacted with azidosugar compounds via a click reaction to introduce different sugar units. Pharmacological activity testing showed that these compounds exhibited strong inhibitory activity against protein tyrosine phosphatase 1B and could be used to prepare PTP1B inhibitors and drugs for the treatment of diabetes. DETAILED DESCRIPTION

[0023] The present invention will be further described in detail below with reference to the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0024] Example 1

[0025] Preparation of oleanane-type triazole glycoside compounds 1 to 22

[0026] 1. Synthesis of compound 24

[0027] Compound 23 (1 g, 1.70 mmol, 1.00 eq.) was dissolved in 35 mL of dichloromethane, and 4-pentynoic acid (330 mg, 3.40 mmol, 2.00 eq.) was added, followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g, 5.61 mmol, 3.30 eq.) and 4-dimethylaminopyridine (61 mg, 0.48 mmol, 0.28 eq.). The reaction was stirred at room temperature for 6 h. After completion of the reaction as monitored by TLC (petroleum ether:ethyl acetate = 2:1), the mixture was filtered and concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 24 (1.08 g, yield 95.0%). Its structural characterization data are as follows: 1 H-NMR (400MHz, CHLOROFORM-D): δ5.94(s,1H),5.36(s,1H),4.52(s,1H),3.66(s,3H),3.35(s,1H),2.98(dq,J=12.7,6.4Hz,1H),2.60-2.44(m,6H),2 .30(s,2H),1.93(dq,J=24.0,4.9,3.0Hz,4H),1.81-1.41(m,15H),1.39-1. 23(m,6H),1.15(s,4H),1.02(d,J=14.6Hz,2H),0.89(s,15H),0.75(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.43,174.14,171.66,145.26,122.73,82.73,81.39, 69.17,55.31,51.64,47.57,46.88,46.39,42.45,42.22,39.50,39.36,38.25,37.85,36.9 7,34.26,34.02,33.97,33.10,32.60,32.40,30.84,29.82,29.17,28.16,27.39,26.70,25.83,24.65,23.88,23.71,18.27,17.03,16.83,15.52,14.67,14.33; HR-MS (ESI): m / z theoretical value C 42 H 65 NO5[M+H + ]:664.4936, measured value 664.4921.

[0028] 2. Synthesis of compounds 1-11

[0029] Compound 24 (120 mg, 0.18 mmol, 1.00 eq.) and azido-β-D-peracetylmannopyranose (0.18 mmol, 1.00 eq.) were dissolved in 1 mL of tert-butanol. CuSO4 (5.78 mg, 0.036 mmol, 0.20 eq.) and sodium ascorbate (15.3 mg, 0.072 mmol, 0.40 eq.) were dissolved in 1 mL of deionized water. The two solutions were then mixed, heated to 40°C, and stirred for 3 h. After the reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 1:1), the solution was diluted with 5 mL of distilled water and extracted three times with ethyl acetate (3 mL × 3). The ethyl acetate phases were combined, washed sequentially with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 80:1) to obtain compound 1.

[0030] The above-mentioned azido β-D-peracetyl pyranose mannoside is replaced in sequence with azido β-D-peracetyl pyranose glucopyranosyl, azido β-D-peracetyl pyranose galactosyl, azido α-L-peracetyl pyranose rhamnosyl, azido α-L-peracetyl pyranose arabinosyl, azido β-D-peracetyl pyranose arabinosyl, azido α-D-peracetyl pyranose xylosyl, azido β-D-peracetyl pyranose xylosyl, azido β-D-peracetyl cellobiosyl, azido β-D-peracetyl pyranose galactosyl (1→4)-α-D-peracetyl pyranose glucopyranosyl, and azido β-D-peracetyl pyranose glucopyranosyl (1→4)-β-D-peracetyl pyranose glucopyranosyl to obtain triazole glycoside compounds 2 to 11 in sequence.

[0031] The structural characterization data of compound 1 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.59(s,1H),6.10(s,1H),5.92(t,J=5.8Hz,1H),5.68(s,1H),5.42-5.19(m,3H),4.47(dd,J=11.0,5.2Hz,1H ),4.35-4.13(m,2H),3.93(dd,J=9.8,6.1Hz,1H),3.66(s,3H),3.35(dq,J=13.9,7.1Hz,1H),3.00(dt,J=22.7,6.8Hz,3H),2.72(t,J=7.3Hz,2H ),2.54-2.45(m,1H),2.30(t,J=7.4Hz,2H),2.21-2.04(m,9H),1.99(s,3H),1.95-1.83(m,3H),1.72(d,J=27.6Hz,5H),1.60(dd,J=17.1,7.5H z,4H),1.47(td,J=16.1,15.3,8.3Hz,5H),1.39-1.23(m,6H),1.16(d,J =12.0Hz,5H),1.02(d,J=13.8Hz,2H),0.95-0.77(m,16H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.28,174.14,172.49,170.66,169.90,169.74,169.22,146.74,145.28,122.70, 120.41,84.81,81.25,75.80,70.99,68.99,65.11,62.38,55.33,51.65,47.59,46.91,46.38,42.44,42.21,39.49,3 9.33,38.25,37.84,36.98,34.26,34.03,33.93,33.12,32.64,32.40,30.86,29.21,28.14,27.39,26.72,25.83,24.66,23.90,23.72,23.66,23.61,21.18,20.88,20.81,20.73,20.63,18.27,17.03,16.81,15.51; HR-MS (ESI): m / z theoretical value C 56 H 84 N4O 14 [M+H + ]:1037.6057, measured value 1037.5978.

[0032] The structural characterization data of compound 2 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.56 (s, 1H), 5.92 (s, 1H), 5.83 (d, J = 8.5Hz, 1H), 5.49-5.30 (m, 3H), 5.22 (t, J = 9. 2Hz,1H),4.50(t,J=8.0Hz,1H),4.28(dd,J=12.9,5.0Hz,1H),4.13(d,J=12.6Hz,1H),3.97(d,J=10.3Hz,1H),3.66( s,3H),3.35(dq,J=13.6,6.9Hz,1H),3.01(dt,J=27.0,6.8Hz,3H),2.72(q,J=7.0Hz,2H),2.49(d,J=13.7Hz,1H),2 .30(t,J=6.5Hz,2H),2.12-2.00(m,10H),1.86(s,6H),1.77-1.56(m,12H),1.28-0.98(m,12H),0.95-0.71(m,21H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.28,174.13,172.37,170.60,170.05,169.50,169.01,147.39,145.29,122.70, 119.51,85.81,81.23,75.21,72.84,70.34,67.85,61.71,55.32,51.64,47.59,46.90,46.39,42.45,42.22,39.50,3 9.33,38.27,37.85,36.98,34.27,34.04,33.95,33.11,32.66,32.41,30.86,29.21,28.13,27.40,26.72,25.82,24.67,23.91,23.72,23.67,23.61,21.27,20.82,20.67,20.65,20.29,18.28,17.04,16.83,15.52; HR-MS (ESI): m / z theoretical value C 56 H 84 N4O 14 [M+H + ]:1037.6057, measured value 1037.6035.

[0033] The structural characterization data of compound 3 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.62(s,1H),5.92(t,J=5.6Hz,1H),5.79(d,J=9.3Hz,1H),5.61-5.45(m,2H),5.36(d,J=4.3Hz,1H), 5.22(d,J=10.4Hz,1H),4.50(t,J=7.9Hz,1H),4.26-4.03(m,3H),3.65(d,J=1.8Hz,3H),3.35(dq,J=13.8,7.0Hz,1H),3.02(dt,J=25. 3,7.3Hz,3H),2.73(q,J=6.9Hz,2H),2.49(dd,J=13.1,4.3Hz,1H),2.30(t,J=7.5Hz,2H),2.21(d,J=1.7Hz,3H),2.02(dd,J=13.8,1.7 Hz,6H),1.94–1.70(m,9H),1.60(tq,J=16.0,8.4,5.1Hz,9H),1.52-1.44(m,4H),1.39-1.11(m,11H),0.94-0.79(m,16H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.28,174.13,172.40,170.45,170.10,169.95,169.17,147.32,145.28,122.68, 119.61,86.33,81.21,74.08,70.97,67.90,66.99,61.30,55.30,51.64,47.58,46.89,46.37,42.43,42.20,39.48,3 9.32,38.26,37.84,36.97,34.25,34.03,33.99,33.11,32.64,32.39,30.85,29.20,28.12,27.38,26.71,25.82,24.66,23.89,23.71,23.65,23.60,21.28,20.80,20.77,20.63,20.39,18.27,17.03,16.83,15.53; HR-MS (ESI): m / z theoretical value C 56 H 84 N4O 14 [M+H + ]:1037.6057, measured value 1037.6035.

[0034] The structural characterization data of compound 4 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.58(s,1H),6.05(s,1H),5.91(d,J=5.8Hz,1H),5.68(s,1H),5.36(d,J=4.0Hz,1H),5.24-5.03(m, 2H), 4.46 (t, J = 8.1Hz, 1H), 3.79 (p, J = 6.6Hz, 1H), 3.66 (d, J = 1.9Hz, 3H), 3.36 (dq, J = 14.2, 7.1Hz, 1H), 3.00 (dq, J = 26.0, 6.9, 6.2Hz, 3 H),2.73(d,J=7.3Hz,2H),2.49(d,J=12.6Hz,1H),2.31(t,J=7.5Hz,2H),2.10(d,J=9.1Hz,5H),2.01-1.87(m,5H),1.81-1.63(m,6H), 1.59(t,J=8.3Hz,5H),1.48(dt,J=14.5,6.8Hz,4H),1.39-1.26(m,7H),1.20(d,J=38.4Hz,5H),1.06-0.89(m,9H),0.86-0.62(m,9H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.24,174.11,172.48,169.98,169.92,169.29,145.25,122.64,120.25,84.76, 81.23,77.48,76.84,74.03,70.94,69.72,69.24,55.25,51.62,47.53,46.85,46.33,42.38,42.17,39.44,39.29,38 .21,37.78,36.92,34.23,34.00,33.94,33.09,32.60,32.34,30.83,29.79,29.17,28.08,27.35,26.68,25.80,24.63,23.86,23.69,23.62,23.58,21.22,20.87,20.75,20.65,18.22,17.64,17.00,16.79,15.48; HR-MS (ESI): m / z theoretical value C 54 H 82 N4O 12 [M+H + ]:979.6002, measured value 979.5917.

[0035] The structural characterization data of compound 5 are: 11H-NMR (400 MHz, chloroform-d): δ 7.64 (s, 1H), 5.92 (t, J = 5.7 Hz, 1H), 5.70 (d, J = 9.1 Hz, 1H), 5.57 (t, J = 9.6 Hz, 1H), 5.46 - 5.29 (m, 2H), 5.22 (dt, J = 10.2, 2.4 Hz, 1H), 4.49 (t, J = 7.9 Hz, 1H), 4.16 (d, J = 13.5 Hz, 1H), 3.92 (d, J = 13.5 Hz, 1H), 3.65 (d, J = 1.9 Hz, 3H), 3.35 (dq, J = 13.8, 7.0 Hz, 1H), 3.02 (dt, J = 25.0, 7.4 Hz, 3H), 2.73 (s, 2H), 2.56 - 2.39 (m, 1H), 2.30 (t, J = 7.4 Hz, 2H), 2.21 (d, J = 1.9 Hz, 3H), 2.02 (d, J = 1.9 Hz, 3H), 1.89 (d, J = 10.5 Hz, 5H), 1.72 (d, J = 27.2 Hz, 5H), 1.59 (tt, J = 14.9, 6.2 Hz, 7H), 1.47 (td, J = 15.2, 14.6, 7.4 Hz, 5H), 1.37 - 1.22 (m, 5H), 1.09 (d, J = 42.6 Hz, 7H), 0.96 – 0.77 (m, 15H), 0.74 (s, 3H); 13 13C-NMR (101 MHz, chloroform-d): δ 178.13, 174.01, 172.27, 170.14, 169.89, 169.08, 145.17, 122.55, 119.46, 86.67, 81.07, 77.38, 77.06, 76.74, 70.59, 68.07, 67.75, 67.25, 55.18, 51.53, 47.45, 46.76, 46.25, 42.30, 42.08, 39.36, 39.19, 38.14, 37.70, 36.84, 34.13, 33.91, 32.99, 32.52, 32.28, 30.74, 29.09, 27.99, 27.27, 26.59, 25.70, 24.54, 23.77, 23.60, 23.53, 23.45, 21.19, 20.97, 20.60, 20.30, 18.15, 16.91, 16.71, 15.39; HR-MS (ESI): m / z calculated for C 53 H 80 N4O 12 [M + H + : 965.5846, found 965.57�0.

[0036] The structural characterization data of compound 6 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.62 (s, 1H), 5.91 (dd, J = 6.5, 4.6Hz, 1H), 5.70 ( d,J=9.2Hz,1H),5.56(t,J=9.6Hz,1H),5.42(dt,J=3.5,1.6Hz,1H),5.39-5.34(m, 1H),5.22(dd,J=10.1,3.4Hz,1H),4.59-4.37(m,1H),4.15(dd,J=13.5,2.1Hz,1H ),3.92(dd,J=13.5,1.3Hz,1H),3.65(s,3H),3.35(dq,J=13.7,7.0Hz,1H),3.10-3 .01(m,2H),2.97(ddt,J=13.7,7.1,3.4Hz,1H),2.72(dd,J=8.3,6.9Hz,2H),2.52 -2.42(m,1H),2.30(t,J=7.4Hz,2H),2.21(s,3H),2.02(s,3H),1.96-1.83(m,6H), 1.79-1.69(m,2H),1.68-1.53(m,9H),1.48(dd,J=15.0,6.9Hz,4H),1.39-1.26(m ,5H),1.14(s,4H),1.01(dt,J=13.9,3.6Hz,2H),0.97-0.77(m,17H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.23,174.11,172.40,170.24,169.99,169.18,147.20,145.27,122.66,11 9.53,86.76,81.19,70.69,68.17,67.86,67.35,55.29,51.63,47.56,46.87,46.35,42.41,42.18,39.46,39.30 ,38.24,37.83,36.94,34.24,34.02,33.99,33.10,32.62,32.38,30.85,29.20,28.16,27.38,26.70,25.80,24.65,23.88,23.70,23.64,23.58,21.29,21.07,20.70,20.40,18.26,17.02,16.82,15.50; HR-MS (ESI): m / z theoretical value C 53 H 80N4O 12 [M+H + ]:965.5846, measured value 965.5823.

[0037] The structural characterization data of compound 7 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.54(s,1H),5.92(t,J=5.6Hz,1H),5.73(d,J=8.5Hz,1H),5.37(dd,J=11.7,8.2Hz,3H),5.17-5.06(m,1H),4. 49(t,J=8.0Hz,1H),4.27(dd,J=11.9,5.7Hz,1H),3.66(d,J=1.9Hz,3H),3.57(t,J=11.1Hz,1H),3.35(dq,J=14.0,7.1Hz,1H),3.01(dt,J=19.5, 7.2Hz,3H),2.83-2.59(m,2H),2.55-2.40(m,1H),2.30(t,J=7.5Hz,2H),2.06(d,J=9.2Hz,6H),1.93(dd,J=19.6,6.2Hz,3H),1.87(s,3H),1.72 (d,J=30.2Hz,4H),1.61(dt,J=15.5,6.5Hz,6H),1.53-1.40(m,5H),1.3 8-1.20(m,7H),1.09(d,J=43.2Hz,6H),0.94-0.78(m,15H),0.75(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.30,174.14,172.37,170.03,169.91,169.10,147.32,145.29,122.70,119. 47,86.41,81.21,72.24,70.48,68.57,65.66,55.29,51.65,47.57,46.89,46.38,42.44,42.21,39.49,39.32,38 .26,37.83,36.97,34.27,34.04,33.98,33.11,32.64,32.40,30.86,29.83,29.21,28.12,27.39,26.72,25.83,24.67,23.90,23.72,23.66,23.58,21.28,20.78,20.74,20.33,18.27,17.04,16.83,15.51; HR-MS (ESI): m / z theoretical value C 53 H80 N4O 12 [M+H + ]:965.5846, measured value 965.5776.

[0038] The structural characterization data of compound 8 are: 1 H-NMR (600MHz, CHLOROFORM-D): δ7.54(s,1H),5.94-5.91(m,1H),5.73(d,J=9.0Hz,1H),5.43-5.27(m,4H),5.19-5.06(m,1H),4.49(dd,J=9.9,6.1H z,1H),4.26(dd,J=11.6,5.7Hz,1H),3.65(s,3H),3.56(dd,J=11.6,10.4H z,1H),3.35(dq,J=13.8,7.1Hz,1H),3.03(td,J=7.4,2.4Hz,2H),2.99-2. 95(m,1H),2.70(t,J=7.6Hz,3H),2.48(dd,J=13.0,4.3Hz,1H),2.30(t,J= 7.5Hz,3H),2.05(d,J=14.0Hz,7H),1.91-1.85(m,6H),1.79-1.66(m,4H), 1.64-1.60(m,4H),1.48-1.44(m,3H),1.32(ddd,J=8.8,4.6,2.8Hz,3H),1 .14(s,4H),1.01(dt,J=13.6,3.5Hz,3H),0.91(s,3H),0.89-0.71(m,18H); 13C-NMR (151MHz, CHLOROFORM-D): δ178.28,174.15,172.38,170.04,169.92,169.10,147.29,145.25,122.68,11 9.45,86.36,81.19,72.16,70.42,68.53,65.61,55.25,51.65,47.52,46.84,46.33,42.38,42.16,39.44,39.29 ,38.20,37.80,36.92,34.22,34.01,33.91,33.10,32.58,32.34,30.84,29.18,28.12,27.34,26.69,25.80,24.63,23.86,23.69,23.62,23.56,21.24,20.78,20.74,20.33,18.23,16.99,16.81,15.49; HR-MS (ESI): m / z theoretical value C 53 H 80 N4O 12 [M+H + ]:965.5846, measured value 965.5829.

[0039] The structural characterization data of compound 9 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.50 (s, 1H), 5.92 (t, J = 5.8Hz, 1H), 5.76 (d, J = 7.6Hz, 1H), 5.37 (dd, J = 6.4, 3.3Hz, 3H), 5.11 (dtd, J = 31.8, 9.4, 2. 1Hz,2H),4.99-4.84(m,1H),4.63-4.43(m,3H),4.38(dt,J=12.7,3.5Hz, 1H),4.19-4.00(m,2H),3.91(q,J=7.6,5.8Hz,2H),3.65(d,J=2.1Hz,4H), 3.35(dq,J=13.5,6.8Hz,1H),3.11-2.87(m,3H),2.70(p,J=8.6,7.7Hz,2 H),2.49(d,J=12.4Hz,1H),2.30(td,J=7.5,2.1Hz,2H),2.20-1.96(m,17H ),1.88(dd,J=20.2,5.9Hz,5H),1.77-1.56(m,12H),1.55-1.39(m,6H),1 .31(dt,J=20.9,13.3Hz,5H),1.09(d,J=43.7Hz,7H),0.96-0.60(m,18H);13 C-NMR (101MHz, CHLOROFORM-D): δ178.28,174.14,172.42,170.61,170.35,170.26,169.67,169.44,169.22,169.19,147.23,145.29, 122.67,119.61,100.95,85.62,81.24,76.00,72.95,72.49,72.25,71.68,70.46,67.83,61.79,61.67,55.30,51.65,47.59,46.89,46 .38,42.43,42.21,39.49,39.32,38.26,37.84,36.96,34.26,34.03,33.92,33.11,32.64,32.39,30.86,29.20,28.11,27.39,26.71,25.82,24.66,23.90,23.71,23.66,23.60,21.23,20.94,20.82,20.67,20.58,20.34,18.27,17.03,16.81,15.52; HR-MS (ESI): m / z theoretical value C 68 H 100 N4O 22 [M+H + ]:1325.6902, measured value 1325.6802.

[0040] The structural characterization data of compound 10 are: 11H-NMR (400 MHz, chloroform-d): δ 7.51 (s, 1H), 5.92 (t, J = 5.7 Hz, 1H), 5.77 (d, J = 7.7 Hz, 1H), 5.37 (d, J = 8.3 Hz, 4H), 5.12 (dd, J = 10.3, 8.1 Hz, 1H), 4.96 (dt, J = 10.6, 2.6 Hz, 1H), 4.62 - 4.39 (m, 3H), 4.25 - 4.05 (m, 3H), 3.90 (q, J = 8.6, 7.5 Hz, 3H), 3.65 (d, J = 1.9 Hz, 3H), 3.35 (dq, J = 14.0, 7.1 Hz, 1H), 3.01 (dt, J = 16.6, 7.3 Hz, 3H), 2.71 (q, J = 6.9 Hz, 2H), 2.55 - 2.45 (m, 1H), 2.30 (t, J = 7.4 Hz, 2H), 2.16 (d, J = 1.9 Hz, 3H), 2.13 - 2.01 (m, 12H), 1.99 - 1.87 (m, 6H), 1.85 (d, J = 1.9 Hz, 3H), 1.72 (d, J = 22.0 Hz, 6H), 1.60 (q, J = 7.6 Hz, 6H), 1.52 - 1.41 (m, 5H), 1.38 - 1.22 (m, 6H), 1.15 (s, 3H), 1.02 (d, J = 13.6 Hz, 2H), 0.94 - 0.73 (m, 18H); 13 13C-NMR (101 MHz, chloroform-d): δ 178.29, 174.15, 172.41, 170.52, 170.33, 170.25, 170.21, 169.64, 169.27, 169.21, 145.29, 122.67, 101.24, 85.59, 81.23, 75.97, 75.75, 72.75, 71.03, 70.95, 70.54, 69.13, 66.67, 61.90, 60.92, 55.29, 51.65, 47.57, 46.88, 46.37, 42.42, 42.20, 39.48, 39.32, 38.25, 37.83, 36.96, 34.25, 34.03, 33.90, 33.11, 32.63, 32.38, 30.85, 29.20, 28.10, 27.38, 26.71, 25.82, 24.65, 23.89, 23.71, 23.65, 21.23, 20.94, 20.85, 20.81, 20.78, 20.76, 20.64, 20.36, 18.26, 17.03, 16.81, 15.51; HR-MS (ESI): m / z calculated for C 68 H 100N4O 22 [M+H + ]:1325.6902, measured value 1325.6718.

[0041] The structural characterization data of compound 11 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.50 (s, 1H), 5.92 (t, J = 5.7Hz, 1H), 5.84 (d, J = 9. 3Hz,1H),5.51-5.41(m,2H),5.34(dtd,J=21.3,10.0,9.3,1.9Hz,3H),5.07(t,J=9 .9Hz,1H),4.87(dt,J=10.8,2.7Hz,1H),4.58-4.39(m,2H),4.24(dt,J=13.3,4.6H z,2H),4.18-4.02(m,2H),3.96(d,J=10.3Hz,2H),3.65(d,J=1.9Hz,3H),3.35(dq,J =14.1,7.1Hz,1H),3.00(dt,J=23.7,6.9Hz,3H),2.71(q,J=6.9Hz,2H),2.49(d,J= 12.3Hz,1H),2.30(td,J=7.5,1.9Hz,2H),2.11(dd,J=8.4,1.9Hz,6H),2.08-2.00( m,11H),1.98-1.87(m,3H),1.83(d,J=1.9Hz,3H),1.80-1.56(m,13H),1.52-1.44( m,4H),1.36-1.23(m,5H),1.15(s,5H),1.02(d,J=13.4Hz,2H),0.95-0.68(m,18H); 13C-NMR (101MHz, CHLOROFORM-D): δ178.29,174.15,172.41,170.73,170.66,170.45,170.08,170.06,169.57,169.34,147.28,145.29,12 2.67,119.60,96.01,85.31,81.24,75.41,75.33,72.51,70.95,70.12,69.32,68.87,68.01,62.66,61.54,55.30,51.65,47.58,46.89, HR-MS (ESI): m / z theoretical value C 68 H 100 N4O 22 [M+H + ]:1325.6902, measured value 1325.6721.

[0042] 3. Synthesis of compounds 12-22

[0043] Compound 1 (60 mg, 1.00 eq) was dissolved in 6 mL of a mixed solvent of methanol and dichloromethane (1:1, V:V). Sodium methoxide was added to adjust the pH to 9, and the reaction was stirred at room temperature for 30 min. After the reaction was completed as monitored by TLC (dichloromethane: methanol = 10:1), the pH was adjusted to 7 using a cation exchange resin. The cation exchange resin was removed by filtration, and the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 30:1) to obtain compound 12.

[0044] The above compound 1 was replaced with equimolar amounts of compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 to obtain compounds 13 to 22 after the acetyl group was removed.

[0045] The structural characterization data of compound 12 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.85(s,1H),5.94(d,J=5.9Hz,1H),5.79(s,1H),5.30(d,J=47.1Hz,4H),4.65-4.14(m,3H), 3.97(s,1H),3.94-3.72(m,3H),3.66(d,J=2.0Hz,3H),3.48(d,J=8.7Hz,1H),3.36(dq,J=13.7,6.9Hz,1H),2.97(dt,J=20.8,7 .0Hz,3H),2.69-2.44(m,6H),2.31(t,J=7.4Hz,2H),2.03-1.84(m,3H),1.68-1.54(m,8H),1.49(q,J=7.5,6.9Hz,4H),1.33(q, J=8.0,7.6Hz,4H),1.16(d,J=15.2Hz,5H),1.01(d,J=12.5Hz,3H),0.91(d,J=6.9Hz,9H),0.81(d,J=11.0Hz,7H),0.74(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.26,174.18,172.85,146.03,145.20,122.62,121.93,86.55, 81.46,79.25,73.60,70.84,65.84,60.92,55.21,51.70,51.66,47.53,46.87,46.32,42.29,42.13, 39.43,39.31,38.18,37.83,36.93,34.21,34.01,33.15,32.66,32.35,30.86,29.82,29.21,28.15,27.38,26.67,25.88,24.63,23.72,21.09,18.26,17.00,16.88,15.51,14.27; HR-MS (ESI): m / z theoretical value C 48 H 76 N4O 10 [M+H + ]:869.5634, measured value 869.5572.

[0046] The structural characterization data of compound 13 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.66(s,1H),5.95(d,J=5.8Hz,1H),5.57(s,2H),5.49(d,J=8.2Hz,1H),5.36( s,1H),4.47(t,J=7.6Hz,2H),4.06(s,1H),3.77(d,J=19.3Hz,3H),3.66(d,J=2.0Hz,3H),3.56(s,1H),3.36(dq, J=13.8,7.0Hz,1H),3.08-2.78(m,4H),2.64-2.48(m,4H),2.31(t,J=7.4Hz,2H),2.19-1.82(m,4H),1.79-1.40( m,15H),1.34(p,J=8.0,6.9Hz,4H),1.26(d,J=12.1Hz,3H),1.15(s,3H),1.06-0.97(m,2H),0.96-0.72(m,18H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.22,174.17,172.66,146.28,145.21,122.60,122.06,87.77, 81.38,78.92,72.47,68.77,68.25,60.96,55.22,51.70,51.65,47.55,46.86,46.32,42.28,42.13, 39.43,38.18,37.84,36.93,34.20,34.01,33.71,33.15,32.67,32.36,30.86,30.42,29.23,28.19,27.38,26.67,25.89,24.63,23.72,20.98,18.26,17.00,16.90,15.52,14.20; HR-MS (ESI): m / z theoretical value C 48 H 76 N4O 10 [M+H + ]:869.5634, measured value 869.5590.

[0047] The structural characterization data of compound 14 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.72(s,1H),5.94(d,J=6.7Hz,1H),5.39(d,J=30.0Hz,3H),5.00(s,1H),4.60-4.01(m,4H) ,3.77(t,J=21.2Hz,3H),3.65(d,J=2.1Hz,4H),3.36(dq,J=13.5,6.7Hz,1H),3.05-2.84(m,3H),2.61(s,3H),2.51(d,J=12. 7Hz,2H),2.31(t,J=7.3Hz,3H),1.84-1.69(m,2H),1.61(dq,J=26.1,9.0,8.1Hz,8H),1.48(p,J=7.6,7.1Hz,5H),1.33(q,J= 7.9,7.5Hz,4H),1.25(s,4H),1.15(s,3H),1.01(d,J=12.0Hz,3H),0.91(d,J=5.5Hz,9H),0.81(d,J=7.9Hz,6H),0.74(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.22,174.15,172.70,146.31,145.22,122.63,122.40,88.36,81 .46,73.91,70.11,68.84,61.03,55.26,51.66,47.57,46.89,46.35,42.32,42.16,39.47,39.33,38. 22,37.86,36.96,34.25,34.02,33.74,33.16,32.71,32.41,30.87,29.82,29.24,28.22,27.42,26.68,25.90,24.64,23.85,23.74,23.65,21.00,18.29,17.03,16.92,15.53,14.26; HR-MS (ESI): m / z theoretical value C 48 H 76 N4O 10 [M+H + ]:869.5634, measured value 869.5568.

[0048] The structural characterization data of compound 15 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.77(s,1H),5.97(t,J=5.7Hz,1H),5.72(s,1H),5.36(s,1H),4.48(t,J=7.9Hz,1H),4.38(s,1H),3.73(d,J= 7.6Hz,1H),3.66(d,J=1.9Hz,3H),3.56(d,J=7.7Hz,2H),3.34(dt,J=14.1,7.0Hz,1H),3.00(t,J=8.0Hz,4H),2.71(d,J=7.6Hz,2H),2.49(dd,J =12.6,4.1Hz,1H),2.31(td,J=7.4,1.9Hz,3H),1.94(dd,J=29.2,11.8Hz,4H),1.85-1.69(m,2H),1.68-1.55(m,8H),1.51-1.44(m,4H),1.35( dd,J=22.9,6.9Hz,7H),1.26(d,J=11.0Hz,2H),1.15(s,4H),1.02(d,J=13.5Hz,3H),0.91(d,J=9.1Hz,9H),0.81(d,J=7.0Hz,7H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.54,174.19,172.68,146.04,145.20,122.76,121.81,86.45 ,81.39,75.40,73.99,72.48,70.40,55.29,51.69,47.56,46.87,46.39,42.40,42.20,39.48,39. 39,38.23,37.85,36.96,34.24,34.01,33.11,32.63,32.38,30.85,29.15,28.16,27.38,26.68,25.84,24.62,23.88,23.71,21.22,18.27,17.80,17.03,16.86,16.11,15.53; HR-MS (ESI): m / z theoretical value C 48 H 76 N4O9[M+H + ]:853.5685, measured value 853.5622.

[0049] The structural characterization data of compound 16 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.66(s,1H),5.94(d,J=5.8Hz,1H),5.35(d,J=16.2Hz,2H),4.82-4.21(m,4H),4.18-3.92(m,3H),3 .88-3.72(m,2H),3.67(d,J=2.0Hz,3H),3.36(dq,J=13.9,7.0Hz,1H),2.99(q,J=6.8,6.4Hz,3H),2.69(d,J=7.6Hz,2H),2.50(d,J=1 1.3Hz,1H),2.32(t,J=7.4Hz,2H),1.91(d,J=9.8Hz,4H),1.80–1.71(m,2H),1.70-1.54(m,9H),1.50(q,J=8.1,7.1Hz,4H),1.34(d,J =8.9Hz,3H),1.27(d,J=10.5Hz,3H),1.15(s,3H),1.03(d,J=13.4Hz,3H),0.92(d,J=7.8Hz,9H),0.82(d,J=8.3Hz,6H),0.75(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.35,174.19,172.66,146.39,145.23,122.68,121.80,88.60 ,81.38,73.61,70.26,68.62,55.25,51.69,47.54,46.86,46.34,42.36,42.16,39.44,39.33,38. 20,37.82,36.93,34.22,34.02,33.87,33.13,32.61,32.35,30.86,29.83,29.19,28.16,27.36,26.68,25.85,24.64,23.85,23.71,23.63,21.09,18.25,17.00,16.86,15.51; HR-MS (ESI): m / z theoretical value C 47 H 74 N4O9[M+H + ]:839.5529, measured value 839.5459.

[0050] The structural characterization data of compound 17 are: 1H-NMR (600MHz, CHLOROFORM-D): δ7.63 (s, 1H), 5.93 (dd, J = 6.4, 4.6Hz, 1H), 5.3 7(t,J=3.6Hz,1H),5.32-5.29(m,1H),4.48(dd,J=9.2,7.0Hz,1H),4.39(t,J=9 .0Hz,1H),4.27(s,1H),4.16(d,J=12.7Hz,1H),4.07(s,1H),3.93(s,1H),3.84 (dd,J=9.2,3.3Hz,1H),3.78(d,J=12.7Hz,1H),3.66(s,4H),3.49(s,1H),3.36( dq,J=13.7,7.0Hz,1H),3.00(dt,J=13.8,6.9Hz,4H),2.70(td,J=7.4,2.5Hz,2 H),2.53-2.47(m,1H),2.31(t,J=7.4Hz,2H),2.01-1.86(m,4H),1.80-1.70(m,2 H),1.66-1.60(m,6H),1.53-1.46(m,5H),1.38-1.30(m,5H),1.15(s,4H),1.03 (d,J=14.1Hz,3H),0.91(d,J=12.7Hz,9H),0.82(d,J=10.6Hz,6H),0.75(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.36,174.18,172.65,146.63,145.28,122.71,121. 47,88.44,81.38,73.51,70.52,69.08,68.36,55.29,51.68,47.59,46.90,46.38,42.42, 42.21,39.49,38.29,37.85,36.97,34.04,33.13,32.64,32.35,30.88,29.20,28.17,27.43,26.72,25.86,24.66,23.73,21.16,18.30,17.04,16.86,15.53; HR-MS (ESI): m / z theoretical value C 47 H 74 N4O9[M+H + ]:839.5529, measured value 839.5510.

[0051] The structural characterization data of compound 18 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.64(s,1H),5.95(d,J=5.8Hz,1H),5.74-5.14(m,3H),4.47(t,J=7.7Hz,3H),4.16-3.66(m ,5H),3.66(d,J=2.1Hz,3H),3.39(dp,J=27.4,7.0,5.7Hz,3H),2.99(t,J=7.0Hz,3H),2.68(t,J=7.5Hz,2H),2.50(d,J=12.5H z,2H),2.31(td,J=7.4,2.0Hz,2H),1.97(d,J=13.5Hz,1H),1.61(dq,J=27.3,11.1,9.6Hz,8H),1.48(p,J=6.6Hz,5H),1.33(q ,J=10.4,7.1Hz,4H),1.26(d,J=9.3Hz,2H),1.16(d,J=16.5Hz,5H),1.02(d,J=13.1Hz,2H),0.96-0.76(m,16H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.37,174.18,172.71,146.68,145.22,122.69,121.66,88.33 ,81.47,72.58,69.33,68.40,64.79,55.27,51.68,47.57,46.89,46.37,42.37,42.18,39.48,39. 36,38.23,37.85,36.97,34.26,34.03,33.91,33.14,32.67,32.40,30.87,29.20,28.19,27.40,26.69,25.88,24.64,24.15,23.73,23.38,21.15,18.27,17.03,16.89,15.52; HR-MS (ESI): m / z theoretical value C 47 H 74 N4O9[M+H + ]:839.5529, measured value 839.5469.

[0052] The structural characterization data of compound 19 are: 1H-NMR (600MHz, CHLOROFORM-D): δ7.64(s,1H),5.96(t,J=5.6Hz,1H),5.41(d,J=8.6Hz,1H),5.33(d,J=38.1Hz,3H),5.12(s,1H),4.75(s, 1H),4.47(t,J=7.9Hz,1H),4.02(s,2H),3.81-3.74(m,1H),3.65(s,5H),3.43(s,1H),3.35(dq,J=13.7,7.0Hz,1H),3.01-2.96(m,3H),2.6 8(q,J=7.1Hz,2H),2.54-2.43(m,2H),2.31(t,J=7.4Hz,2H),2.05-1.83(m,4H),1.80-1.67(m,3H),1.64-1.61(m,3H),1.58(s,2H),1.48(h ept,J=6.8,6.2Hz,6H),1.34-1.31(m,3H),1.14(s,4H),1.01(d,J=12.7Hz,3H),0.90(d,J=7.9Hz,9H),0.80(d,J=9.8Hz,6H),0.73(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.40,174.19,172.65,146.61,145.19,122.68,121.72,88.28, 81.41,72.47,69.29,68.39,55.22,51.69,47.52,46.85,46.34,42.33,42.14,39.43,39.34,38.18, 37.82,36.92,34.21,34.01,33.87,33.13,32.61,32.34,30.85,29.83,29.18,28.16,27.36,26.67,25.85,24.62,23.85,23.71,23.62,22.82,21.12,18.25,17.00,16.86,15.50; HR-MS (ESI): m / z theoretical value C 47 H 74 N4O9[M+H + ]:839.5529, measured value 839.5510.

[0053] The structural characterization data of compound 20 are: 1H-NMR (400MHz, METHANOL-D4): δ7.97(d,J=2.1Hz,1H),7.24(t,J=5.8Hz,1H),5.59(dd,J=9.3,2.1Hz,1H),5.35(s,1H),4.69-4.24( m,3H),4.01-3.84(m,4H),3.84-3.52(m,8H),3.38(d,J=9.0Hz,2H),3.32-3.11(m,5H),3.05(dt,J=23.2,7.0Hz,3H),2.76(dt,J=22. 5,9.0Hz,3H),2.32(td,J=7.3,2.1Hz,2H),2.03(d,J=13.8Hz,1H),1.96-1.88(m,2H),1.78(t,J=13.4Hz,2H),1.61(dq,J=16.9,7.7 Hz,9H),1.48(d,J=7.4Hz,3H),1.42-1.37(m,1H),1.31(dd,J=15.2,8.3Hz,5H),1.18(s,6H),1.07-1.01(m,2H),1.00-0.66(m,21H); 13 C-NMR (101MHz, METHANOL-D4): δ180.24,175.78,173.93,147.55,145.40,123.82,122.67,104.56,89.22,82. 64,79.61,79.48,78.14,77.82,76.82,74.87,73.68,71.35,62.45,61.44,56.68,52.02,47.65,47.49,42.93, 42.57,40.67,40.58,39.28,38.77,38.08,35.11,34.69,34.35,33.75,33.58,31.63,30.77,30.08,28.65,28.51,27.67,26.48,25.69,24.55,24.50,24.05,23.97,21.96,19.29,17.96,17.25,15.93; HR-MS (ESI): m / z theoretical value C 54 H 86 N4O 15 [M+H + ]:1031.6162, measured value 1031.6016.

[0054] The structural characterization data of compound 21 are: 1H-NMR (400MHz, METHANOL-D4): δ7.97(d,J=1.9Hz,1H),7.24(t,J=5.5Hz,1H),5.59(d,J=9.2Hz,1H),5.35(s,1H),4.61( s,1H),4.52-4.30(m,2H),4.06-3.43(m,15H),3.30(d,J=2.5Hz,3H),3.19(dt,J=13.4,6.7Hz,1H),3.05(dt,J=23.0,7.0 Hz,3H),2.75(dt,J=15.2,8.9Hz,3H),2.32(td,J=7.4,1.9Hz,2H),2.05(t,J=12.9Hz,1H),1.99-1.86(m,2H),1.78(t,J =13.4Hz,2H),1.68-1.45(m,14H),1.41(d,J=8.7Hz,2H),1.31(dd,J=15.1,8.3Hz,4H),1.18(s,6H),1.08-0.55(m,21H); 13 C-NMR (101MHz, METHANOL-D4): δ180.25,175.78,173.94,147.55,145.40,123.82,122.70,105.07,89.24,82 .64,79.64,79.47,77.14,76.84,74.79,73.61,72.52,70.29,62.52,61.51,56.68,52.02,47.65,47.49,42. 93,42.57,40.67,40.58,39.29,38.77,38.08,35.11,34.69,34.35,33.75,33.58,31.63,30.08,28.64,28.51,27.67,26.47,25.69,24.55,24.50,24.04,23.96,21.96,19.29,17.96,17.24,15.92; HR-MS (ESI): m / z theoretical value C 54 H 86 N4O 15 [M+H + ]:1031.6162, measured value 1031.6016.

[0055] The structural characterization data of compound 22 are: 1H-NMR (400MHz, METHANOL-D4): δ7.97(s,1H),7.24(t,J=5.8Hz,1H),5.58(d,J=8.9Hz,1H),5.35(s,1H),5.24( s,1H),4.71-4.36(m,2H),3.99-3.42(m,15H),3.35-3.13(m,5H),3.05(dt,J=23.6,7.1Hz,3H),2.76(dt,J=22. 9,5.9Hz,3H),2.32(t,J=7.4Hz,2H),2.05(t,J=12.6Hz,1H),1.98-1.86(m,2H),1.78(t,J=13.5Hz,2H),1.62(d d,J=14.7,8.1Hz,9H),1.55-1.42(m,6H),1.31(dd,J=15.3,8.3Hz,4H),1.21-1.05(m,6H),1.04-0.69(m,21H); 13 C-NMR (101MHz, METHANOL-D4): δ180.26,175.79,173.95,147.56,145.41,123.82,122.70,102.93,89.33,82. 65,80.28,79.56,78.22,75.06,74.87,74.16,73.58,71.47,62.73,61.83,56.69,52.02,47.65,47.50,42.93, 42.58,40.67,40.58,39.28,38.77,38.08,35.11,34.69,34.35,33.75,33.57,31.63,30.78,30.09,28.64,28.51,27.67,26.46,25.69,24.55,24.50,24.04,23.96,21.96,19.29,17.96,17.24,15.92; HR-MS (ESI): m / z theoretical value C 54 H 86 N4O 15 [M+H + ]:1031.6162, measured value 1031.6021.

[0056] Table 1 Substituents and yields of compounds 1 to 22

[0057]

[0058]

[0059]

[0060] Example 2

[0061] Application of the oleanane-type azaglycoside compound of the present invention in the preparation of PTP1B inhibitors and antidiabetic drugs

[0062] Compounds 1 to 22 synthesized in the above examples were used as test compounds to test their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B). The specific test results are as follows:

[0063] A 200 μL reaction system contained recombinant PTP1B, buffer (25 mM HEPES, 50 mM NaCl, 2.5 mM EDTA, 0.1% BSA, pH 7.2), and the test compound. A blank control (without PTP1B or test compound) and a negative control (without test compound) were also established. The reaction was incubated at 37°C for 10 min. The protein tyrosine phosphatase substrate PNPP was added and the reaction continued at 37°C for an additional 30 min. The reaction was terminated by adding a 2M Na₂CO₃ aqueous solution, and the OD value was measured at 405 nm. The inhibition rate was calculated based on the OD value: Inhibition rate = [1 - (OD sample - OD blank) / (OD negative - OD blank)] × 100%. The results are shown in Table 2.

[0064] Table 2 In vitro PTP1B inhibitory activity of compounds 1 to 22

[0065]

[0066]

[0067] As can be seen from the activity results in Table 2, the oleanane-type triazole glycoside compound of the present invention exhibits excellent inhibitory activity against protein tyrosine phosphatase 1B, which is significantly better than the positive control sodium orthovanadate, and is also better than the best 6-iodoperacetyl D-mannosyl substituted oleanane-type glycoside compound (Compound 2) disclosed in CN117720610 A. It can be used to prepare protein tyrosine phosphatase 1B inhibitors and drugs for treating diabetes.

Claims

1. An oleanane-type triazole glycoside compound, characterized in that: The structural formula of the compound is shown below: wherein R is selected from any one of D-peracetylmannasyl, D-peracetylglucosyl, D-peracetygalactosyl, L-peracetyrhamnosyl, L-peracetyarabinosyl, D-peracetyarabinosyl, L-peracetyxylosyl, D-peracetyxylosyl, D-peracetylcellobiosyl, D-peracetygalactose (1→4)-D-peracetylglucosyl, D-peracetylglucosyl (1→4)-D-peracetylglucosyl, D-mannosyl, D-glucosyl, D-galactosyl, L-rhamnosyl, L-arabinosyl, D-arabinosyl, L-xylosyl, D-xylosyl, D-cellobiosyl, D-galactose (1→4)-D-glucosyl, and D-glucose (1→4)-D-glucosyl.

2. The oleanane-type triazole glycoside compound according to claim 1, characterized in that: The R is selected from β-D-peracetylated mannopyranosyl, β-D-peracetylated glucopyranosyl, β-D-peracetylated galactopyranosyl, α-L-peracetylated rhamnosyl, α-L-peracetylated arabinopyranosyl, β-D-peracetylated arabinopyranosyl, α-L-peracetylated xylopyranosyl, β-D-peracetylated xylopyranosyl, β-D-peracetylated cellobiosyl, β-D-peracetylated galactopyranosyl (1→4)-α-D-peracetylated glucopyranosyl, β-D-peracetylated glucopyranosyl, Any one of (1→4)-β-D-peracetylated glucopyranosyl, β-D-mannopyranosyl, β-D-glucopyranosyl, β-D-galactopyranosyl, α-L-rhamnopyranosyl, α-L-arabinopyranosyl, β-D-arabinopyranosyl, α-L-xylopyranosyl, β-D-xylopyranosyl, β-D-cellobiosyl, β-D-galactopyranosyl (1→4)-α-D-glucopyranosyl, and β-D-glucopyranosyl (1→4)-β-D-glucopyranosyl.

3. Use of the oleanane-type triazole glycoside compound according to claim 1 in the preparation of a PTP1B inhibitor.

4. Use of the oleanane-type triazole glycoside compound according to claim 1 in the preparation of antidiabetic drugs.

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